This grant supports research into four areas related to the effects of cardiovascular disease, tuberculosis, renal transplantation and drug interaction on several drugs important in clinical therapy. The pharmacokinetics of digoxin in heart failure patients and whether there is a change in pharmacokinetics that parallels the clinical improvement of the patient will be investigated by administering simultaneously an i.v. injection of labeled digoxin and an oral dose of nonradioactive drug. During therapy and at different steady-state serum concentrations, the concentration-response relationship will be evaluated using non-invasive techniques. The kinetics of ethambutol will be studied in three groups of tuberculosis patients: those with normal renal function, those with renal impairment, and patients with end-stage renal disease. Using specific and sensitive HPLC assays for azathioprine and its active metabolite, 6-mercaptopurine, pharmacokinetic studies will be carried out in monkeys, dogs, and renal transplant patients. Measures of immunosuppressive activity will be carried out using a modification of the mixed lymphocyte reaction. Attempts will be made to correlate measures of immunosuppressive activity with drug pharmacokinetics. An approximately two- to three-fold plasma increase in plasma indomethacin concentration occurs in patients receiving concurrent probenecid. The pharmacokinetics of this drug interaction will be examined in a number of animal models as well as in human volunteers and in rheumatoid arthritis patients. Assay techniques will be developed to measure specifically indomethacin and its metabolites in both biological tissues and fluids.